Catecholamines are diabetogenic hormones secreted during stress. We have recently demonstrated that norepinephrine exerts most of its ketogenic activity independent of its lipolytic effect. The proposed studies will define the mechanism(s) of norepinephrine's ketogenic activity and assess its importance to the pathogenesis of diabetic ketoacidosis. The proposed studies will be completed in four phases. Phase I will examine the contribution of catecholamine-induced glucagon secretion to norepinephrine's overall ketogenic activity. In these studies, somatostatin will be infused to inhibit norepinephrine induced glucagon secretion. Phase II will examine the site(s) at which norepinephrine exerts its ketogenic activity (production versus utilization). A continuous infusion of DL-Beta-hydroxybutyrate will be used to determine the effect of norepinephrine on the metabolic clearance rate of ketone bodies. Phase III will resolve whether norepinephrine's ketogenic activity is mediated via alpha or beta adrenergic receptors. These in vivo studies will be completed using selective pharmacological alpha and beta stimulation (phenylehrine will be infused as the alpha adrenergic agonist and isoproteronal as the beta adrenergic agonist). Phase IV of the proposed studies will determine the importance of catecholamines to the pathogenesis of insulin withdrawal, stress-induced diabetic ketoacidosis. These studies will involve the administration of anti-insulin serum and bacterial pyrogen to induce stress ketoacidosis in rats which have been either treated or not treated with pharmacological adrenergic blockade. Comparison of the rate of rise in plasma glucose and ketone body concentration during these stress studies will be indicative of the contribution of catecholamines to diabetic ketoacidosis. These proposed studies are important since little is known about norepinephrine's ketogenic activity (in contrast to its lipolytic activity). The ability of the catecholamines at physiological concentrations to suppress endogenous insulin secretion and to stimulate endogenous glucagon secretion make these hormones the most potentially ketogenic of all of the stress hormones in vivo.